chr4-5793606-A-G
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_153717.3(EVC):c.1777-2A>G variant causes a splice acceptor, intron change. The variant allele was found at a frequency of 0.00000645 in 1,551,412 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 2/2 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★).
Frequency
Consequence
NM_153717.3 splice_acceptor, intron
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
EVC | ENST00000264956.11 | c.1777-2A>G | splice_acceptor_variant, intron_variant | Intron 12 of 20 | 1 | NM_153717.3 | ENSP00000264956.6 | |||
EVC | ENST00000506240.1 | n.93A>G | non_coding_transcript_exon_variant | Exon 1 of 2 | 3 | |||||
CRMP1 | ENST00000506216.5 | n.1647+31888T>C | intron_variant | Intron 12 of 12 | 5 | |||||
EVC | ENST00000515113.1 | n.-2A>G | upstream_gene_variant | 5 |
Frequencies
GnomAD3 genomes AF: 0.0000131 AC: 2AN: 152214Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.00000640 AC: 1AN: 156284Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 82290
GnomAD4 exome AF: 0.00000572 AC: 8AN: 1399198Hom.: 0 Cov.: 29 AF XY: 0.00000724 AC XY: 5AN XY: 690198
GnomAD4 genome AF: 0.0000131 AC: 2AN: 152214Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0AN XY: 74360
ClinVar
Submissions by phenotype
Ellis-van Creveld syndrome;C0457013:Curry-Hall syndrome Pathogenic:2
This sequence change affects an acceptor splice site in intron 12 of the EVC gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in EVC are known to be pathogenic (PMID: 23220543). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. Disruption of this splice site has been observed in individuals with Ellis-van Creveld syndrome (PMID: 17024374, 23220543). This variant is also known as IVS12-2A > G. ClinVar contains an entry for this variant (Variation ID: 551792). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. -
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Ellis-van Creveld syndrome Pathogenic:2
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not provided Pathogenic:1
EVC: PVS1, PM2 -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at